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Blood. 2019 May 17. pii: blood.2019000626. doi: 10.1182/blood.2019000626. [Epub ahead of print]

Recurrent MSC E116K mutations in ALK-negative anaplastic large cell lymphoma.

Author information

1
Laboratory Medicine and Pathology, Mayo Clinic, United States.
2
Genomic Sciences and Precision Medicine Center, Medical College of Wisconsin, United States.
3
Hematology, Mayo Clinic in Rochester, United States.
4
Health Sciences Research, Mayo Clinic, United States.
5
Mayo Clinic.
6
Mayo Clinic, United States.
7
Tongji Hospital, Tongji University School of Medicine, China.
8
Center for Individualized Medicine, Mayo Clinic, United States.
9
Children's Hospital of Philadelphia, United States.
10
Pathology and Laboratory Medicine, Rhode Island Hospital, United States.
11
PATHOLOGY AND LABORATORY MEDICINE, UHS HOSPITALS, United States.
12
Pathology and Laboratory Medicine, Mayo Clinic Florida, United States.
13
Department of Internal Medicine, University of Iowa, United States.
14
Univ of Iowa, United States.
15
Department of Pathology, Spedali Civili, Brescia, Italy, Italy.
16
Hematology, Mayo Clinic, United States.
17
Physiology and Biomedical Engineering, Mayo Clinic, United States.
18
Health Sciences Research, Mayo Clinic College of Medicine, United States.
19
Division of Hematology and Internal Medicine, Mayo Clinic, United States.
20
Laboratory Medicine and Pathology, Mayo Clinic, United States feldman.andrew@mayo.edu.

Abstract

Anaplastic large cell lymphomas (ALCLs) represent a relatively common group of T-cell non-Hodgkin lymphomas (T-NHLs) that are unified by similar pathologic features but demonstrate marked genetic heterogeneity. ALCLs are broadly classified as being ALK-positive or ALK-negative, based on the presence or absence of ALK rearrangements. Exome sequencing of 62 T-NHLs identified a previously unreported recurrent mutation in the musculin gene, MSC E116K, exclusively in ALK-negative ALCLs. Additional sequencing for a total of 238 T-NHLs confirmed the specificity of MSC E116K for ALK-negative ALCL and further demonstrated that 14/15 mutated cases (93%) had co-existing DUSP22 rearrangements. Musculin is a basic helix-loop-helix (bHLH) transcription factor that heterodimerizes with other bHLH proteins to regulate lymphocyte development. The E116K mutation localized to the DNA binding domain of musculin and permitted formation of musculin-bHLH heterodimers but prevented their binding to authentic target sequence. Functional analysis showed MSCE116K acted in a dominant-negative fashion, reversing wild-type musculin-induced repression of MYC and cell cycle inhibition. Chromatin immunoprecipitation-sequencing and transcriptome analysis identified the cell-cycle regulatory gene E2F2 as a direct transcriptional target of musculin. MSCE116K reversed E2F2-induced cell cycle arrest and promoted expression of the CD30-IRF4-MYC axis, while its expression was reciprocally induced by binding of IRF4 to the MSC promoter. Finally, ALCL cells expressing MSC E116K were preferentially targeted by the BET inhibitor JQ1. These findings identify a novel, recurrent MSC mutation as a key driver of the CD30-IRF4-MYC axis and cell cycle progression in a unique subset of ALCLs.

PMID:
31101622
DOI:
10.1182/blood.2019000626

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